Pinostilbene as a Potential Cytotoxic Agent in Cancer Cell Lines: Improvement of Solubility and Stability by Cyclodextrin Encapsulation

<b>Background/Objectives:</b> Pinostilbene is a naturally occurring methoxylated stilbene with many beneficial health properties, including antioxidant, antimicrobial and neuroprotective activities. This stilbene has also been shown to possess anticancer or cytotoxic activity in some cancers. As in the case of other stilbenes, pinostilbene is very labile, degrades rapidly under stress conditions and is poorly water-soluble, which poses a drawback to its use as a drug. This work aims to provide further insights into its cytotoxicity activity in a colon cancer cell line and to overcome its physicochemical limitations by encapsulating the molecule in cyclodextrins. <b>Methods:</b> The anticancer activity was evaluated in vitro in Caco-2 colorectal cells using the neutral red assay. Subsequently, a screening of cyclodextrins was carried out to determine the one with the highest encapsulation constant, as well as the encapsulation stoichiometry, using fluorescence spectroscopy and molecular docking predictions. The formation of the inclusion complexes was checked by differential scanning calorimetry and scanning electron microscopy. The protective effect of cyclodextrins on pinostilbene release was monitored through spectrophotometric measurements over time. <b>Results:</b> Pinostilbene showed in vitro cytotoxicity activity in Caco-2 colorectal cells by the neutral red assay. This study revealed that the cyclodextrin with the highest encapsulation constant was the hydroxypropyl-β-cyclodextrin (K_F = 10,074.45 ± 503.72 M^-1), and the encapsulation stoichiometry was 1:1. DSC and SEM assays confirmed the formation of these inclusion complexes. Cyclodextrins were able to satisfactorily reduce pinostilbene degradation from 31% to less than 15% after 3 months, as well as increase its water solubility up to 10 times and enhance its release as a function of the pH of the medium. <b>Conclusions:</b> Pinostilbene is a promising drug candidate with strong in vitro antiproliferative activity. Many of its physicochemical limitations can be overcome with cyclodextrins, which opens the door to its future use in the pharmaceutical and food industries.